This project is based on the recent finding from our laboratory that diffuse aggressive lymphomas have a striking propensity to use the immunoglobulin VH4.21 gene for their antigen binding receptor. We have found, in a limited series of unselected patients, that 11 out of 18 of these tumors express an immunoglobulin heavy chain that was derived from the VH4.21 gene. Most of these VH genes expressed by the tumor cells contain mutations with respect to their germ line counterparts, and almost all of these mutations had occurred prior to the clonal expansion of th tumor. This finding contrasts with our previous findings in follicular lymphomas, where no bias toward any particular V region gene has been noted, and where ongoing somatic mutation occurs during clonal expansion of the follicular lymphoma tumors. Thus follicular lymphomas and diffuse large cell lymphomas are biologically distinct diseases. Whereas follicular lymphoma appears to develop as a random hit within the normal B cell population, diffuse large cell lymphoma appears to arise from a directed hit on a restricted set of cells expressing particular VH genes. Furthermore, whereas follicular lymphomas frequently generate nucleic acid mutations within their expressed immunoglobulin genes as the tumor clone expands possible under the influence of continuing stimulation by an antigen, diffuse large cell lymphoma tumors do not alter their immunoglobulin genes as the tumor expands. A second provocative finding has been that immunoglobulin proteins using the VH4.21 gene can have a binding activity and a killing activity on human B cells. This finding leads to a number of hypotheses about the role of the VH4.21 gene in the pathogenesis of diffuse large cell lymphoma. In this project we will: 1. determine the true prevalence of VH4.21 gene expression in diffuse aggressive B cell lymphomas, 2. determine whether the expression of VH4.21 correlates with clinical or biological parameters of the tumors such as exact histologic type, clinical outcome and activation of other genes within the tumor such as bcl-6, myc or bcl-23. determine whether the protein products produced by the tumors bind to specific autoantigens, in particular antigens on B lymphocytes, 4. determine whether these proteins produced by the tumors have a killing activity on B lymphocytes and whether this killing activity extends to the tumor cells which have produced these proteins. These findings should lead to a better understanding of the pathogenesis of diffuse aggressive B cell lymphoma and may provide approaches to the construction of diagnostic probes and therapeutic strategies for the treatment of this disease.